Etubics Corporation

Patent Trials and Appeals Board

Jul 29, 2020

15265709 - (D) (P.T.A.B. Jul. 29, 2020)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
15/265,709 09/14/2016 Joseph P. Balint 8774ETU-1-
PCT-C1-CON-1
6123
157773 7590 07/29/2020
Sheridan Ross PC
1560 Broadway
Suite 1200
Denver, CO 80202
EXAMINER
ZEMAN, ROBERT A
ART UNIT PAPER NUMBER
1645
NOTIFICATION DATE DELIVERY MODE
07/29/2020 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
e-docket@sheridanross.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JOSEPH P. BALINT, FRANK R. JONES, and
RICHARD B. GAYLE1
Appeal 2020-002719
Application 15/265,709
Technology Center 1600
Before ERIC B. GRIMES, FRANCISCO C. PRATS, and
TAWEN CHANG, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to an
adenovirus vector, which have been rejected as obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
STATEMENT OF THE CASE
One aspect of the invention provides a method of generating an
immune response against one or more target antigens in an

1 Appellant identifies the real party in interest as Etubics Corporation.
Appeal Br. 3. We use the word “Appellant” to refer to “applicant” as defined
in 37 C.F.R. § 1.42(a).
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individual comprising administering to the individual an
adenovirus vector comprising: a) a replication defective
adenovirus vector, wherein the adenovirus vector has a deletion
in the E2b region, and b) a nucleic acid encoding the one or
more target antigens; and readministering the adenovirus vector
at least once to the individual; thereby generating an immune
response against the one or more target antigens.
Spec.2 ¶ 8.
“Target antigens of the present invention include but are not limited to
antigens derived from a variety of tumor proteins. Illustrative tumor proteins
useful in the present invention include . . . Her2/neu.” Id. ¶ 112.
Claims 37, 39–46, 49, 50, 54, 65, and 66 are on appeal. Claim 37,
reproduced below, is illustrative:
37. A composition comprising a replication defective
adenovirus vector comprising:
a deletion in an E2b region of the replication defective
adenovirus vector; and
a nucleic acid sequence encoding a tumor associated
antigen, wherein the tumor associated antigen is a Her2/neu
antigen.

The claims stand rejected as follows:
Claims 37, 39–46, 49, 50, 54, 65, and 66 under 35 U.S.C. § 103(a) as
obvious based on Monaci ’5863 and Chamberlain4 (Ans. 3);
Claims 37, 39–46, 49, 50, 54, 65, and 66 under 35 U.S.C. § 103(a) as
obvious based on Monaci WO5 and Chamberlain (Ans. 4);

2 Substitute Specification filed November 28, 2016.
3 US 7,662,586 B2, issued Feb. 16, 2010.
4 US 6,083,750, issued July 4, 2000.
5 WO 2005/012527 A1, published Feb. 10, 2005.
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Claims 37, 39–46, 49, 50, 54, 65, and 66 under 35 U.S.C. § 103(a) as
obvious based on Monaci WO, Chamberlain, and Sastry6 (Ans. 6);
Claims 37, 39–46, 49, 50, 54, 65, and 66 under 35 U.S.C. § 103(a) as
obvious based on Monaci ’586 and Amalfitano7 (Ans. 8);
Claims 37, 39–46, 49, 50, 54, 65, and 66 under 35 U.S.C. § 103(a) as
obvious based on Monaci WO and Amalfitano (Ans. 9);
Claims 37, 39–46, 49, 50, 54, 65, and 66 under 35 U.S.C. § 103(a) as
obvious based on Monaci WO, Amalfitano, and Sastry (Ans. 11).
OPINION
The Examiner has rejected all of the claims as obvious based on one
of the Monaci references, combined with either Chamberlain or Amalfitano,
and optionally with Sastry. Appellant provides substantive arguments only
with respect to the combination of Monaci ’586 and Chamberlain, and relies
on those arguments with respect to all of the other rejections as well. See
Appeal Br. 12–15. Because the same issues are relevant to all of the
rejections, and because Appellant relies on the same arguments for all of the
rejections, we will consider the rejections together.
Monaci ’586 states that it is a continuation of application 10/565,418,
“filed as application No. PCT/EP2004/008234.” Monaci ’586, front page. The
International Application Number of Monaci WO is PCT/EP2004/008234.
Monaci WO, front page. Thus, the disclosures of the Monaci references are
the same, and we will refer only to Monaci ’586.

6 US 7,410,758 B2, issued Aug. 12, 2008.
7 Production and Characterization of Improved Adenovirus Vectors with the
E1, E2b, and E3 Genes Deleted, Journal of Virology, 72(2):926–33 (1998).
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Monaci ’586 discloses “polynucleotides encoding human HER2
protein . . . codon-optimized for high level expression in a human cell.”
Monaci ’586 3:10–15. Monaci ’586 also “provides adenoviral and plasmid-
based vectors comprising the synthetic polynucleotides and discloses use of
said vectors in immunogenic compositions and vaccines for the prevention
and/or treatment of HER2-associated cancer.” Id. at 3:16–20.
More specifically, Monaci ’586 discloses that its “nucleic acids . . .
may be assembled into an expression cassette which comprises sequences
designed to provide for efficient expression of the protein in a human cell.”
Id. at 13:51–54. “If the vector chosen is an adenovirus, it is preferred that the
vector be a so-called first-generation adenoviral vector. These adenoviral
vectors are characterized by having a non-functional E1 gene region, and
preferably a deleted adenoviral E1 gene region.” Id. at 14:10–14. “[T]he
vectors . . . may be used in immunogenic compositions and vaccines for
preventing the development of adenocarcinomas associated with aberrant
HER2 expression and/or for treatment of existing cancers. The vectors of the
present invention allow for vaccine development and commercialization.”
Id. at 14:65 to 15:3.
Monaci ’586 does not disclose adenoviral vectors with a deletion in an
E2b region, but Chamberlain does. See Chamberlain 4:19–21. Chamberlain
states that “[e]xisting Ad vectors have been shown to be problematic in vivo
. . . in part because current or first generation Ad vectors are deleted for only
the early region 1 (E1) genes.” Id. at 13:10–12. By contrast, Chamberlain’s
“invention provides Ad vectors containing deletions in the E2b region.” Id.
at 13:40–41.
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Chamberlain states that “when genes critical to the viral life cycle are
deleted (e.g., the E2b genes), a further crippling of Ad to replicate and
express other viral gene proteins occurs. This decreases immune recognition
of virally infected cells, and allows for extended durations of foreign gene
expression.” Id. at 13:61–66. Chamberlain also states that “[t]he most
important attribute of E1, polymerase and preterminal protein deleted
vectors[8] . . . is their inability to express the respective proteins, as well as a
predicted lack of expression of most of the viral structural proteins.” Id. at
13:66 to 14:2. “The polymerase and preterminal proteins are absolutely
required for Ad replication . . . and thus their deletion is extremely
detrimental to Ad vector late gene expression.” Id. at 14:13–17.
Amalfitano similarly discloses “an improved Ad vector that
incorporated deletions not only in the Ad E1 and E3 genes . . . but also the
Ad polymerase (E2b) gene.” Amalfitano 928, left col. Amalfitano discloses
that “AdΔpol vectors . . . have a theoretically decreased potential to generate
replication-competent Ad (RCA), since multiple recombination events are
required to regenerate a viable virus containing both the E1 and polymerase
gene functions.” Id. at 931, right col. Amalfitano also discloses that “the
AdΔpol vectors . . . have a significantly decreased potential to express viral
late genes such as the Ad fiber protein compared with first-generation Ad
vectors. Isolation of an Ad vector with a decreased potential to express viral
epitopes may improve gene transfer in vivo.” Id. at 932, left col.

8 The “E2b region compris[es] the DNA polymerase and the adenovirus
preterminal protein gene.” Chamberlain 4:22–24.
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Based on the above teachings, it would have been obvious to combine
Monaci ’586’s HER2-encoding gene with the E2b-deleted adenoviral vector
disclosed by Chamberlain or Amalfitano because Monaci ’586 expressly
suggests using an adenoviral vector to express HER2 to prevent or treat
HER2-associated cancers, and both Chamberlain and Amalfitano disclose
the advantages of adenoviral vectors having a deletion in an E2b region.
Specifically, Chamberlain discloses that such vectors are defective in the
expression of viral proteins, resulting in decreased immune recognition and
extended duration of foreign gene expression, and Amalfitano discloses that
they have decreased potential to express viral late genes, and thus decreased
potential to express viral epitopes, which may improve in vivo gene transfer.
Appellant argues that “[e]xperimental results in the application as
filed, together with Dr. Amalfitano’s declaration,[9] establish that the
claimed composition can successfully elicit specific immunity by
homologous re-administration and that this result was unexpected to skilled
persons at the time of invention.” Appeal Br. 7. “Homologous
readministration” refers to administering the same antigen-expressing vector
to a patient multiple times. See Spec. ¶ 5 (“[M]ost investigators using First
Generation Ad5 vector vaccines use the approach of a heterologous prime-
boost regimen. . . . This . . . results in a subsequent immune response against
Ad5 such that one cannot administer a further re-immunization (boost) with
the same (or a different) adenovirus vector vaccine that utilizes the same
viral backbone.”); ¶ 7 (“[T]here is no homologous vaccine delivery vector

9 Declaration under 37 C.F.R. § 1.132 of Andrea Amalfitano, filed January
16, 2018.
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that can be employed in a prime reimmunization protocol for vaccination.
The present invention provides this and other advantages.”).
Appellant argues that the Specification’s “Example 5 demonstrates
that the claimed composition can successfully generate an effective immune
response in a homologous re-administration protocol.” Appeal Br. 7.
Appellant points to the Amalfitano Declaration as evidence that “this
property of the claimed composition was unexpected.” Id. Appellant argues
that “Dr. Amalfitano explains that she ‘did not believe that these replication
defective adenovirus vectors could be useful to generate immune responses
to target antigens where re-administered to a subject multiple times’” and
that “such understanding was the state of the art at the time of invention.”
Id., citing the Amalfitano Decl. ¶¶ 4, 5. Appellant argues that “Dr.
Amalfitano’s declaration—made under oath and citing to documented
evidence of ideas that were in circulation among workers in this field at the
time of invention—constitutes evidence of the unexpected nature of
Appellant’s discoveries.” Id. at 7–8.
We have considered the evidence cited by Appellant—including the
Specification’s Example 5, the Amalfitano Declaration, and the Draper
reference10 cited therein—but find that a preponderance of the evidence
supports a conclusion of obviousness. Appellant cites the Specification’s
Example 5 as evidence of unexpected results. That example describes an
experiment “show[ing] that multiple immunizations of Ad5 immune mice
with Ad5 [E1-, E2b-]-HER2 induced HER2 specific cell mediated immune

10 Draper et al., Viruses as vaccine vectors for infectious diseases and
cancer, Nature Reviews Microbiology 8:62–73 (2010).
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responses and antibody responses that had beneficial effects on tumor
progression.” Spec. ¶ 175.
More specifically, the example reports that “elevated numbers of
IFN-γ and IL-2 secreting cells were observed . . . after two immunizations
with Ad5 [E1-, E2b-]-HER2. Moreover, the highest numbers of IFN-γ and
IL-2 secreting cells were observed after the third immunization.” Id. ¶ 182.
The example also states that “increasing quantities of detectable antibody to
HER2 were observed after one, two, and three immunizations with Ad5
[E1-, E2b-]-HER2, with the greatest quantities of antibody observed after
the third immunization.” Id. ¶ 184. Finally, the example states that “Ad5
immune mice immunized with Ad5 [E1-, E2b-]-HER2 can significantly
slow the progress of tumor growth after a lethal challenge of HER2
expressing tumor cells.” Id. ¶ 187.
The Specification does not, however, characterize the results of
Example 5 as surprising or unexpected. See id. ¶¶ 175–187.
Dr. Amalfitano states that her “article (Amalfitano et al.) disclosed
new vectors that may be useful for gene therapy applications.” Amalfitano
Decl. ¶ 4 (referring to the same Amalfitano reference cited by the Examiner;
see id. ¶ 3). Dr. Amalfitano states that, based on her experience, she “did not
believe that these replication defective adenovirus vectors could be useful to
generate immune responses to target antigens when re-administered to a
subject multiple times.” Id.
Dr. Amalfitano does not identify the time at which she “did not
believe” that the vectors described in the Amalfitano reference would be
effective if re-administered to a subject. Based on the declaration, we
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interpret Dr. Amalfitano’s statement to refer to the time at which the
Amalfitano reference was published, which was February 1998. The
effective filing date of the instant application, however, is July 2, 2007.
Spec. ¶ 1.
Dr. Amalfitano also states that, “[a]t the time of the claimed invention
in the instant application,[11] it was my opinion that because an immune
response is generated to immunogenic capsid proteins . . . , the effectiveness
of adenoviruses as vaccine vectors would have been limited to heterologous
immunization methods.” Amalfitano Decl. ¶ 5. This statement, however,
refers to “adenoviruses” generally, not adenoviruses with a deletion in an
E2b region, as recited in the claims on appeal.
Similarly, Dr. Amalfitano states that “[i]t is my opinion that the same
adenovirus vector generally may not be used for both the first and second
immunizations.” Id. This statement again does not specifically address
adenoviruses with a deletion in the E2b region, as claimed.
Dr. Amalfitano refers to Draper as evidence that “host responses to
the structural proteins of the viral vector itself were known to diminish
responses against the vaccine insert (target antigen) when the same vector
was used for multiple immunizations.” Amalfitano Decl. ¶ 5. Dr. Amalfitano
does not cite to any specific disclosure in Draper, which is a review of
“viruses as vaccine vectors.” Draper 62, abstract. Draper addresses
adenovirus vectors generally (see id. at 63, Table 1) and states that

11 The Amalfitano Declaration was originally filed in a different application
(12/651,836; see Amalfitano Decl., page 1) but the instant application is a
continuation of a continuation of that application, so the effective filing
dates are the same. Spec. ¶ 1.
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heterologous prime-boost protocols with different viral vectors have been
tested (id. at 64, right col.), but does not appear to address adenoviral vectors
with a deletion in an E2b region, as claimed.
Dr. Amalfitano concludes that “it is [her] opinion that one would not
have expected to generate an effective immune response to one or more
target antigens using a homologous immunization protocol where the same
replication defective adenovirus vector used for the first administration is re-
administered to the subject in the second administration.” Amalfitano Decl.
¶ 5. Once again, however, Dr. Amalfitano refers generally to “replication
defective adenovirus vector[s],” rather than specifically addressing the
vector recited in the claims: an adenovirus vector comprising a deletion in an
E2b region.
In summary, the example in the Specification cited by Appellant does
not state that the results found were unexpected or surprising, and neither the
Amalfitano Declaration nor the Draper reference addresses what would have
been expected for an adenoviral vector with a deletion in the E2b region, as
of the effective filing date of the instant application. We conclude that
Appellant’s evidence is entitled to little probative weight as a showing of
unexpected results.
Weighing against Appellant’s evidence is Chamberlain’s disclosure
that a deletion in the E2b region of an adenoviral vector would be expected
to “crippl[e]” the ability of the adenovirus to express other genes, which
“decreases immune recognition of virally infected cells, and allows for
extended durations of foreign gene expression.” Chamberlain 13:61–66.
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Chamberlain also states that E2b-deleted adenoviral vectors were expected
to be unable to express most viral structural proteins. Id. at 13:66 to 14:2.
Similarly, the Amalfitano reference states that AdΔpol vectors (i.e.,
adenoviral vectors with a deletion in the E2b region) “have a significantly
decreased potential to express viral late genes” and “a decreased potential to
express viral epitopes,” which “may improve gene transfer in vivo.”
Amalfitano 932, left col.
The statements in Chamberlain and the Amalfitano reference
specifically address what would have been expected for adenoviral vectors
with a deletion in the E2b region, and indicate that such vectors were
expected to cause decreased immune recognition and decreased expression
of viral epitopes, as well as extended duration of foreign gene expression
and improved in vivo gene transfer. Based on these teachings, a skilled
artisan would reasonably expect that an E2b-deleted adenoviral vector would
be less likely to provoke an immune response to adenoviral gene products,
and therefore would be more likely to be useful for multiple administrations,
compared to a first generation (E1-deleted) adenoviral vector.
In summary, the evidence cited by the Examiner supports a prima
facie case of obviousness, and the evidence submitted by Appellant to show
nonobviousness is entitled to little probative weight because it does not
specifically address the claimed invention as of the effective filing date. We
conclude that a preponderance of the evidence supports the Examiner’s
rejections, which we therefore affirm.
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DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
37, 39–46,
49, 50, 54,
65, 66
103(a) Monaci ’586,
Chamberlain
37, 39–46,
49, 50, 54,
65, 66

37, 39–46,
49, 50, 54,
65, 66
103(a) Monaci WO,
Chamberlain
37, 39–46,
49, 50, 54,
65, 66

37, 39–46,
49, 50, 54,
65, 66
103(a) Monaci WO,
Chamberlain, Sastry
37, 39–46,
49, 50, 54,
65, 66

37, 39–46,
49, 50, 54,
65, 66
103(a) Monaci ’586,
Amalfitano
37, 39–46,
49, 50, 54,
65, 66

37, 39–46,
49, 50, 54,
65, 66
103(a) Monaci WO,
Amalfitano
37, 39–46,
49, 50, 54,
65, 66

37, 39–46,
49, 50, 54,
65, 66
103(a) Monaci WO,
Amalfitano, Sastry
37, 39–46,
49, 50, 54,
65, 66

Overall
Outcome
37, 39–46,
49, 50, 54,
65, 66

TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R.
§ 1.136(a)(1)(iv).
AFFIRMED